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Aspirin worsens exercise performance and pulmonary gas exchange in patients with heart failure who are taking angiotensin-converting enzyme inhibitors
Aspirin worsens exercise performance and pulmonary gas exchange in patients with heart failure who are taking angiotensin-converting enzyme inhibitors Marco Guazzi, MD, Gianluca Pontone, MD, and Piergiuseppe Agostoni, MD Milan, Italy
Background Pulmonary function abnormalities participate in causing exercise disability in patients with congestive heart failure (CHF). Impaired pulmonary gas transfer is one of these abnormalities. Angiotensin-converting enzyme (ACE) inhibitors improve diffusion for carbon monoxide and exercise capacity, an effect that is seemingly mediated through prostaglandin activation because it is inhibited by cyclooxygenase blockade with aspirin. This suggests the possibility that aspirin may disturb the pulmonary function and exercise ability in CHF, at least in those patients who are taking ACE inhibitors. This study was aimed at probing this hypothesis. Methods A dose of 325 mg aspirin was given daily for 8 weeks to 26 consecutive patients with primary dilated cardiomyopathy (New York Heart Association class II or III) whose current outpatient antifailure therapy included (group 1, 18 cases) or did not include (group 2, 8 cases) an ACE inhibitor in addition to digoxin and furosemide. During the study ACE inhibition was continued in group 1 by giving enalapril 20 mg daily.
Results Tests repeated at 8 weeks proved that aspirin was deleterious in group 1. Compared with run-in, rest carbon dioxide, peak exercise oxygen uptake (peak VO2), and tidal volume levels were diminished in this group; the ratio of exercise minute ventilation to carbon dioxide production (VE/VCO2) was augmented and its variations were inversely related to those of peak VO2. Similar results were not observed in group 2; however, once this part of the study was completed and enalapril was included in the current therapeutic regimen, an inhibitory effect of aspirin on carbon dioxide, peak VO2, peak tidal volume, and VE/VCO2 at 1 L levels became evident and was similar to that observed in group 1. Conclusions Aspirin does not affect ventilation efficiency and peak VO2 in patients with CHF not taking ACE inhibitors, but it worsens the pulmonary diffusion for carbon monoxide, VO2, and the ventilatory response to exercise in the presence of ACE inhibition. This may be relevant in patients with CHF from ischemic heart disease. Whether the same may be true of smaller aspirin doses was not investigated in this study. (Am Heart J 1999;138:254-60.)
See related Editorial on page 193. The effects of prostaglandins include preservation of endothelial integrity, capillary tone, and permeability.1 Because bradykinin-mediated prostaglandin synthesis is quite susceptible to cyclooxygenase blockers such as From the Istituto di Cardiologia dell’Università degli Studi, Centro di Studio per le Ricerche Cardiovascolari del Consiglio Nazionale delle Ricerche, Fondazione “Monzino”, IRCCS. Supported in part by a grant from the National Research Council, Rome, and the Monzino Foundation, Milan. Presented in part at the 70th American Heart Association Scientific Sessions, Orlando, Fla, November 9-13, 1997. Submitted February 23, 1998; accepted June 17, 1998. Reprint requests: Marco Guazzi, MD, Istituto di Cardiologia, Via C. Parea, 4, 20138 Milan, Italy. E-mail: [email protected] Copyright © 1999 by Mosby, Inc. 0002-8703/99/$8.00 + 0 4/1/96660
aspirin, these agents are used for exploring the pathophysiologic importance of prostaglandins in various clinical settings.2 Congestive heart failure (CHF) is an example of prostaglandin synthesis activation,3 and some of the benefits of angiotensin-converting enzyme (ACE) inhibitors in patients with CHF may be interfered with by cyclooxygenase blockers.4-6 Thus the question has emerged of whether in the case of potential clinical indication, aspirin is safe when the heart is failing and ACE inhibitors are included in the therapy.7 There seems to be the premise for an exposure of the lungs to the counteractive activity of aspirin because the luminal surface of the lung vessels is an important site of prostaglandin production, release, and metabolism.8 An example may be the improvement produced by enalapril of pulmonary diffusion for carbon monoxide in CHF and its disappearance with the administration of aspirin.9 Because abnormal ventilation is a major cause of exercise disability in CHF,10 it seems reasonable to wonder
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Guazzi, Pontone, and Agostoni 255
Table I. Drug treatments and hemodynamic and respiratory data at rest in groups 1 and 2 in the run-in period and after aspirin combination
Run-in No. of patients Enalapril (mg/d) Furosemide (mg/d) Digoxin (mg/d) LV ejection fraction (%) Right ventricular systolic pressure (mm Hg) FEV1 (L) % predicted VC (L) % predicted DLCO (mL/min/mm Hg) % predicted Aspirin Aspirin (mg/d) Enalapril (mg/d) Furosemide (mg/d) Digoxin (mg/d) LV ejection fraction (%) Right ventricular systolic pressure (mm Hg) FEV1 (L) % predicted VC (liters) % predicted DLCO (mL/min/mm Hg) % predicted
Group 1
Group 2
18 20 75 ± 50 0.20 ± 0.7 35 ± 6 28 ± 2
8 — 60 ± 45 0.17 ± 0.7 27 ± 8 31 ± 3
2.6 ± 0.5 85.5 ± 17 3.1 ± 0.6 76 ± 14 22 ± 6 80 ± 16
2.6 ± 0.5 85.5 ± 12 3.2 ± 0.6 78 ± 10 20 ± 4 72 ± 15
325 20 75 ± 50 0.20 ± 0.7 33 ± 7 30 ± 3
325 — 60 ± 45 0.17 ± 0.7 28 ± 6 32 ± 4
2.6 ± 0.5 85.5 ± 15 3 ± 0.6 75 ± 14 19 ± 6* 72 ± 14*
2.6 ± 0.4 82.5 ± 15 3.2 ± 0.6 78.5 ± 11 20 ± 5 72 ± 15
Values are mean ± SD. *P < .05 vs the run-in period.
whether aspirin may disturb pulmonary function and exercise capacity in CHF, at least in subjects who are receiving ACE inhibitors. This study was aimed at probing this possibility by simply giving aspirin to patients with CHF whose current therapeutic regimen did or did not include an ACE inhibitor.
Methods Patients We investigated consecutive patients referred to the Institute of Cardiology, University of Milan, for evaluation of chronic heart failure. They were included in the study if they did not have a history (>10 years) of smoking; had not received aspirin or other cyclooxygenase inhibitors in the previous 3 months; did not have joint disease or peripheral vascular disease that limited exercise; or had forced expiratory volume in 1 sec of >70% of predicted normal value. We assessed 20 patients with stable CHF in New York Heart Association (NYHA) class II to III attributable to idiopathic cardiomyopathy whose current therapeutic regimen included an ACE inhibitor (group 1, mean age 61 ± 7 years) and 8 similar patients (group 2, mean age 60 ± 4 years) who had not received ACE inhibitors in the previous 3 months. Two patients in each group were women. Patients in group 1 had
Figure 1
Study design.
been taking ACE inhibitors from at least 2 years before the study. Informed consent was obtained from each patient and the study design was approved by the Ethics Committee of the Institute of Cardiology, University of Milan.
Pulmonary function tests Measurements of forced expiratory volume in 1 second (FEV1), vital capacity (VC), maximal voluntary ventilation (MVV), and diffusing lung capacity for carbon monoxide (DLCO) were made with the Sensor Medics 2200 Pulmonary Function Test System. Measured diffusing capacity was corrected for anemia by the equation of Cotes et al.11 DLCO was measured in triplicate, with washout intervals of at least 4 minutes (the average was taken as the final result), in a sitting position with a standard single-breath technique with 0.28% carbon monoxide as a test gas. These data are expressed in absolute values and as a percentage of predicted normal values on the basis of standard nomograms incorporating age, sex, height, and weight.
Exercise testing with expiratory gases Patients exercised while sitting on an isokinetic bicycle ergometer with contemporary measurements of respiratory gases; an individualized ramp test was utilized with the ramp rate set to elicit a test duration of approximately 10 minutes. Individual maximal oxygen uptake was considered during a baseline test for determining the ramp rate. Exercise was discontinued when the patient was unable to maintain the imposed workload because of dyspnea or fatigue (symptomlimited exercise). Anaerobic threshold was defined by V-slope analysis. Expired carbon dioxide, oxygen, and volume were measured at rest and throughout exercise with a single-breath analysis with model 2900 from Sensor Medics. Ventilation was assessed by correlating minute ventilation with minute carbon dioxide production (VE/VCO2). Oxygen consumption at peak exercise (peak VO2) and VO2 at the anaerobic threshold are expressed as the oxygen consumption during the 30 seconds in which the examined event occurred. The ratio of the rate of aerobic respiration increase (δVO2 to the rate of watt of
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256 Guazzi, Pontone, and Agostoni
Figure 2
Peak VO2 and tidal volume (VTp) at peak exercise, exercise tolerance time (TT), and ratio of ventilation to carbon dioxide production (VE/VCO2) at 1 L in group 1 at the end of run-in period (Pre) and after (Post) 8 weeks of administration of aspirin. Triangles, NYHA class II; circles, NYHA class III; *P < .01 vs before aspirin; #P = .02 vs before aspirin.
work (δWR) increase during exercise was taken as an index of the aerobically regenerated adenosine triphosphate.10
Hemodynamic evaluation A phased-array echocardiographic Doppler system (Model Sonos 2000 Hewlett Packard), equipped with 25- or 35-MHz transducers for M-mode and 2-dimensional recording and 2.0or 2.5-MHz transducers for Doppler echocardiography, was used for assessing right ventricular systolic pressure and left ventricular ejection fraction according to Simpson’s rule.
maximal exercise test were repeated. After completion of this part of the study, enalapril (10 mg twice daily) was added to furosemide and digoxin in group 2 as a routine antifailure therapy. These patients regularly attended our outpatient heart failure clinic; they repeated pulmonary and exercise testing after an interval of 3 to 5 months, during which treatment was kept constant. Then aspirin (325 mg daily) was combined again and a reevaluation was carried out within 4 weeks. Investigators performing the tests were blinded to the drug administration and results of the previous tests.
Statistical analysis Study design Fifty percent of patients in groups 1 and 2 were in NYHA class II; the remaining patients in both groups were in class III (Figure 1). Two patients in group 1 did not complete the study for personal reasons, and their data were not included in the results. In the 2 week run-in period, each patient was twice subjected to pulmonary function evaluation and maximal exercise test: once at the beginning (for familiarization with the procedure) and once at the end of run-in (control measurements). Optimal doses of furosemide and digoxin were continued in both groups and the ACE inhibitor used in group 1 was enalapril (10 mg twice daily). After run-in, aspirin (325 mg daily) was given for 8 weeks; at the end of this period pulmonary function evaluation and a
Data are expressed as mean ± 1 SD. The effects of aspirin on variables at rest and variables recorded during exercise were analyzed by 2-way analysis of variance for repeated measures. Significant differences were further analyzed with the paired and unpaired t test and, as appropriate, with Bonferroni’s correction. Statistical significance was defined as P < .05. Linear regression analysis was used to examine the correlation between aspirin-induced changes in peak VO2 and the relation of minute ventilation with minute carbon dioxide production.
Results Table I reports NYHA functional class, therapeutic, hemodynamic, and spirometric data in patients in groups
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Figure 3
Peak VO2 and tidal volume (VT p) at peak exercise, exercise tolerance time (TT), and ratio of ventilation to carbon dioxide production (VE/VCO2) at 1 L in group 2 at the end of run-in period (Pre) and after (Post) 8 weeks of administration of aspirin. Triangles, NYHA class II; circles, NYHA class III.
1 and 2 at the end of run-in and in the next 8 weeks, during which aspirin was given according to the study design depicted in Figure 1. There were no group differences in the baseline, and DLCO level in group 1 was the only variable that worsened during this interval with the addition of aspirin. Figures 2 and 3 show that aspirin was deleterious when added in the presence (group 1, Figure 2) and not in the absence (group 2, Figure 3) of the ACE inhibitor enalapril. The effects of aspirin in group 1 consisted of a decrease in exercise tolerance time, peak exercise oxygen uptake and tidal volume, and of an increase in the relation of minute ventilation to carbon dioxide production. The response to aspirin was similar in patients in NYHA class II and III. The variations were not associated with changes in peak exercise heart rate, blood pressure, oxygen uptake per cardiac beat (oxygen pulse, a parameter reliably reflecting variations in stroke volume during exercise), ratio of δVO2 to δWR, and in the oxygen consumption at the anaerobic threshold (Table II). Figure 4 shows that in patients receiving enalapril there was an inverse correlation between the variations with aspirin in peak VO2 and those in the ratio of minute ventilation to minute carbon dioxide production at peak exercise. Table III reports the means of DLCO, peak VO2, peak VT, and VE/VCO2 at 1 L
in group 2 at the end of run-in, after aspirin alone, after enalapril alone, and in combination with aspirin. It is shown that when patients were taking ACE inhibitors, aspirin exerted a negative influence on these variables.
Discussion This study demonstrates that aspirin worsens the ventilatory gas exchange and exercise capacity in patients with CHF taking ACE inhibitors. Exercise is probably the most powerful physiologic stimulus capable of increasing the vascular prostacyclin production rate through an endothelial shear stress mechanism.12 Prostaglandins have been recognized to be involved in determining the physical performance of normal subjects.13
Previous studies In chronic heart failure the augmented production of vasodilating prostaglandins mediates a regional and systemic vasodilating activity, attenuates neurohumoral activation, and counteracts vasoconstriction induced by angiotensin II,14 norepinephrine,15 and endothelins.15 Cyclooxygenase inhibition causes a loss of these counterregulatory mechanisms and may favor a progressive deterioration of patients with advanced heart failure.3
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258 Guazzi, Pontone, and Agostoni
Table II. Heart rate, blood pressure, and oxygen uptake during exercise in groups 1 and 2 at the end of the run-in period and after aspirin combination
Run-in Heart rate peak (beats/min) Blood pressure peak (mm Hg) Systolic Diastolic Oxygen pulse peak (mL/beat) VO2 at anaerobic threshold (mL/min/kg) δVO2/δWR peak (mL/min/w) Aspirin Heart rate peak (beats/min) Blood pressure peak (mm Hg) Systolic Diastolic Oxygen pulse peak (mL/beat) VO2 at anaerobic threshold (mL/min/kg) δVO2/δWR peak (mL/min/w)
Group 1
Group 2
142 ± 9
143 ± 12
172 ± 17 115 ± 15 9.5 ± 3 11 ± 2
175 ± 22 120 ± 15 9±4 11 ± 3
7.5 ± 1.0
7.5 ± 1.2
139 ± 11
141 ± 10
176 ± 17 116 ± 14 10.2 ± 3 12.2 ± 2
180 ± 20 120 ± 14 9.7 ± 3 11.5 ± 3
7.3 ± 1.2
7.4 ± 1.2
Figure 4
Relation between changes (δ) from run-in with aspirin in peak VO2 and changes in VE/VCO2 in group 1.
Values are mean ± SD.
Table III. Pulmonary diffusion, exercise oxygen uptake, tidal volume and ventilation in group 2 in the run-in period and after administration of aspirin, enalapril, and the combination
DLCO (mL/min/mm Hg) Peak VO2 (mL/min/kg) Peak tidal volume (mL/min) VE/VCO2 1 L
Run-in
Aspirin
Enalapril
20 ± 4 17.3 ± 4 1.70 ± 0.3 39 ± 8.2
20 ± 5 17.1 ± 3.8 1.64 ± 0.3 38.1 ± 8.1
23 ± 3* 20 ± 3* 1.80 ± 0.4* 32 ± 8*
Enalapril + Aspirin 20.4 ± 4† 17.5 ± 3† 1.68 ± 0.4† 39.3 ± 8†
Values are mean ± SD. *P < .01 vs run-in period. †P < .05 vs enalapril.
Although a prostaglandin-mediated activity seems to be a common final mechanism of action of several cardiovascular drugs, including diuretics, nitrates, and nitroprusside, ACE inhibitors peculiarly potentiate the cascade of this system. This study addresses the clinical relevance of a potentiation of these mediators through ACE inhibition and of a counteraction, as occurring with the combination of aspirin, in the presence of left ventricular dysfunction and exercise intolerance.
This study Several considerations support the interpretation that a link exists between the beneficial action of enalapril on respiratory function and exercise performance and counteraction of aspirin, and that prostaglandins are the mediators of this link. The 2 groups of patients had similar clinical characteristics, ejection fraction, pulmonary function, and right ventricular systolic pressure.16 That inability to show an effect of aspirin in patients not taking ACE inhibitors (group 2) may have been caused by the small
number of subjects studied is convincingly disproved by the occurrence of an inhibitory activity when aspirin was reintroduced after the combination of enalapril. According to the inclusion of the ACE inhibitor in the therapy, a decline in pulmonary diffusion was noted with aspirin. This could have been caused by removal of an action on alveolar-capillary membrane facilitating conductance or to a decrease in pulmonary capillary blood volume from the known vasodilating properties of prostaglandins. These changes were associated with a decline in peak exercise oxygen uptake, in agreement with the concept that pulmonary diffusion limitation may be a mediator of the exercise oxygen uptake.9,17 When patients were receiving ACE inhibitors, pulmonary gas exchange efficiency was also depressed by aspirin. In fact, tidal volume during exercise was reduced and the ventilatory requirement for given carbon dioxide production was increased. That the lungs are sensitive to prostaglandins and exercise unmasks their involvement is supported by experimental obser-
American Heart Journal Volume 138, Number 2, Part 1
vations showing that increase in blood flow velocity (causing an increase in shear stress) contributes to prostaglandin production in the pulmonary circulation and that a preliminary infusion of indomethacin counteracts this effect.18 It seems, therefore, that in patients with heart failure receiving ACE inhibitors lung prostaglandin production is enhanced and its inhibition with aspirin is deleterious. An important participation of changes in the systemic hemodynamics during exercise as a cause of exercise intolerance seems unlikely because of the absence of significant variations in blood pressure, heart rate, and oxygen pulse at peak exercise. Metabolic reasons were also seemingly excludable because oxygen consumption at the anaerobic threshold and the ratio of peak δVO2 to peak δWR did not vary with aspirin. Although it has been shown that aspirin may reduce blood flow to working muscles,19 the possibility that a reduced efficiency in gas exchange performance may be a substrate for the reduced exercise capacity is supported by the close inverse correlation that was found between variations in peak VO2 and changes in the ratio of minute ventilation to carbon dioxide production.
Clinical implications Thus this study expands the observations made in a previous report from our group.9 It shows that (1) an interference with the enhanced prostaglandin release has well-defined clinical correlates that are similar in NYHA functional class II and III; (2) the prostaglandin stimulating activity of ACE inhibitors is sustained (they, in fact, had been part of the therapeutic management for at least 2 years in group 1); and (3) aspirin counteraction is unrelated to the duration of the ACE inhibitor therapy. The evaluation of the prognostic significance of the counterregulatory effect of aspirin versus ACE inhibition is not an easy item. Aspirin improves the outcome in the acute phase of unstable angina or myocardial infarction20 and is a cornerstone in the primary and secondary prevention of ischemic events.21 ACE inhibitors, on the other hand, improve survival rate,22 quality of life, and exercise performance23 in patients with left ventricular dysfunction. Because ischemic heart disease is a predominant cause of heart failure, it is expected that this drug combination exerts additive beneficial effects. However, a retrospective analysis of the CONSENSUS II trial4 has given support to the finding previously emerged in the SOLVD trial,3,24 that the survival rate curve was different when analysis was performed according to aspirin use or nonuse in patients taking ACE inhibitors. Hall et al5 demonstrated an attenuating action of aspirin on the acute hemodynamic changes with enalapril. Other studies,25 on the contrary, have pointed out that the vasodilating effects of ACE inhibitors are mainly related to blockade of the angiotensin system and that a contrasting effect on vas-
Guazzi, Pontone, and Agostoni 259
cular resistance remains controversial. According to findings in this mid-term exercise study, aspirin subtracts the beneficial action of ACE inhibitors on peak VO2, an independent prognostic predictor in patients with heart failure.26
Limitations Interpretation of findings in this study is potentially weakened by the lack of measurements of plasma prostaglandins. These compounds have a very short half-life (less than 3 minutes) and are not reliably measurable. In addition, their production rate is tissue dependent, and monitoring changes in the pulmonary microvessels during exercise is a difficult task. Investigations in human beings and animals are mainly restricted to an analysis of variations deriving from prostaglandin blockade with cyclooxygenase inhibitors. Whether a lower dose of aspirin would equally show an antagonism remains to be defined.
Conclusions This study indicates that cyclooxygenase prostaglandin blockade with aspirin does not affect ventilation and oxygen consumption during exercise in patients with CHF not taking ACE inhibitors but worsens the pulmonary diffusion capacity and makes the ventilatory response to exercise (tidal volume, ventilation to carbon dioxide production) less effective in those who do, regardless of the duration of ACE inhibition.
References 1. Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev 1979;30:293-331. 2. Cannon PJ. Prostaglandins in congestive heart failure and the effects of nonsteroidal anti-infiammatory drugs. Am J Med 1986;81(suppl 2B):123-31. 3. Dzau VJ, Creager MA. Prostaglandins in congestive heart failure. In: Robertson JIS, Nicholls MG, editors. The renin-angiotensin system. London: Gower; 1986. p. 12-16. 4. Nguyen KN, Aursnes I, Kyekshus J. Interaction between enalapril and aspirin on mortality after acute myocardial infarction: subgroup analysis of the Cooperative new Scandinavian Enalapril Survival Study II (CONSENSUS II). Am J Cardiol 1997;79:115-9. 5. Hall D, Zeitler H, Rudolph W. Counteraction of the vasodilator effects of enalapril by aspirin in severe heart failure. J Am Coll Cardiol 1992;20:1549-55. 6. Guazzi MD, Campodonico J, Celeste F, Guazzi M, Santambrogio G, Rossi M, et al. Antihypertensive efficacy of angiotensin converting enzyme inhibition and aspirin counteraction. Clin Pharmacol Ther 1998;63:79-86. 7. Cleland JGF, Bulpitt CJ, Falk RH, Findlay IN, Oakley CM, Murray G, et al. Is aspirin safe for patients with heart failure? Br Heart J 1995;74:215-9. 8. Hyman AL, Kadowitz PJ. Pulmonary vasodilator activity of prostacyclin (PGI2) in the cat. Circ Res 1979;45:404-9. 9. Guazzi M, Marenzi GC, Alimento M, Contini M, Agostoni PG. Improvement of alveolar-capillary membrane diffusing capacity with
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enalapril in chronic heart failure and counteracting effect of aspirin. Circulation 1997;95:1930-6. Wasserman K, Zhang Y, Gitt A, Belardinelli R, Koike A, Lubarsky L, et al. Lung function and exercise gas exchange in chronic heart failure. Circulation 1997;96:2221-7. Cotes JE, Dabbs JM, Elwood PC, Hall AM, McDonald A, Saunders MJ. Iron deficiency anemia: its effect on transfer factor for the lung (diffusing capacity) and ventilation and cardiac frequency during submaximal exercise. Clin Sci 1972;42:325-35. Niebaure J, Cooke JP. Cardiovascular effects of exercise: role of endothelial shear stress. J Am Coll Cardiol 1996;28:1652-60. Wilson JR, Kapoor SC. Contribution of prostaglandins to exerciseinduced vasodilatation in humans. Am J Physiol 1993;265: H171-H175. Messina EJ, Weiner R, Kaley G. Inhibition of bradykinin vasodilation and potentation of norepinephrine and angiotensin vasoconstriction by inhibitors of prostaglandin synthesis in skeletal muscle of the rat. Circ Res 1975;37:430-7. McGiff JC, Carrol MA, Escalante B. Arachidonate metabolites and kinins in blood pressure regulation. Hypertension 1991;18(suppl III):150-7. Delcroix M, Melot C, Lejeune P, Leeman M, Naeije R. Cyclooxygenase inhibition aggravates pulmonary hypertension and deteriorates gas exchange in canine pulmonary embolism. Am Rev Resp Dis 1992;145:806-10. Puri S, Baker L, Dutka DP, Oakley CM, Hughens JMB, Cleland JGF. Reduced alveolar-capillary membrane diffusing capacity in chronic heart failure: its pathophysiological relevance and relationship to exercise performance. Circulation 1995;91:2769-74. van Grondelle A, Worthen GS, Ellis D, Mathias MM, Murphy RC, Strife RJ, et al. Altering hydrodynamic variables influences PGI2 production by isolated lungs and endothelial cells. J Appl Physiol 1984;57:388-95.
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19. Cowley AJ, Stainer K, Rowley JM, Wilkox RY. Effects of aspirin and indomethacin on exercise-induced changes in blood pressure and limb blood flow in normal volunteers. Cardiovasc Res 1985;19:177-80. 20. ISIS II Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17,187 cases of suspected acute myocardial infarction. ISIS II. Lancet 1988;2:349-60. 21. Antiplatelet Trialists’ Collaboration: secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 1988;296:320-31. 22. SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293-302. 23. Creager MA, Massie BM, Faxon DP, Friedman SD, Krame BL, Weiner BA, et al. Acute and long-term effects of enalapril on the cardiovascular response to exercise and exercise tolerance in patients with congestive heart failure. J Am Coll Cardiol 1985; 6:163-73. 24. Al-Khadza AS, Salem DN, Rand WM, Udelson JE, Smith JJ, Konstam MA. Antiplatelet agents and survival: a cohort analysis from the studies of left ventricular dysfunction (SOLVD) trial. J Am Coll Cardiol 1998;31:419–25. 25. Kiowski W, Beermann J, Rickenbacher P, Haemmerli R, Thomas M, Burkart F, et al. Angiotensinergic versus nonangiotensinergic hemodynamic effects of converting enzyme inhibition in patients with chronic heart failure. Assessment by acute renin and converting enzyme inhibition. Circulation 1994;90:2748-56. 26. Cohn JN, Johnson GR, Shabetai R, Loeb H, Tristani F, Rector T, et al for the V-HeFT VA cooperative Studies Group. Ejection fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrhythmias and plasma norepinephrine as determinants of prognosis in heart failure. Circulation 1993;87(suppl VI):5-16.
Background Pulmonary function abnormalities participate in causing exercise disability in patients with congestive heart failure (CHF). Impaired pulmonary gas transfer is one of these abnormalities. Angiotensin-converting enzyme (ACE) inhibitors improve diffusion for carbon monoxide and exercise capacity, an effect that is seemingly mediated through prostaglandin activation because it is inhibited by cyclooxygenase blockade with aspirin. This suggests the possibility that aspirin may disturb the pulmonary function and exercise ability in CHF, at least in those patients who are taking ACE inhibitors. This study was aimed at probing this hypothesis. Methods A dose of 325 mg aspirin was given daily for 8 weeks to 26 consecutive patients with primary dilated cardiomyopathy (New York Heart Association class II or III) whose current outpatient antifailure therapy included (group 1, 18 cases) or did not include (group 2, 8 cases) an ACE inhibitor in addition to digoxin and furosemide. During the study ACE inhibition was continued in group 1 by giving enalapril 20 mg daily.
Results Tests repeated at 8 weeks proved that aspirin was deleterious in group 1. Compared with run-in, rest carbon dioxide, peak exercise oxygen uptake (peak VO2), and tidal volume levels were diminished in this group; the ratio of exercise minute ventilation to carbon dioxide production (VE/VCO2) was augmented and its variations were inversely related to those of peak VO2. Similar results were not observed in group 2; however, once this part of the study was completed and enalapril was included in the current therapeutic regimen, an inhibitory effect of aspirin on carbon dioxide, peak VO2, peak tidal volume, and VE/VCO2 at 1 L levels became evident and was similar to that observed in group 1. Conclusions Aspirin does not affect ventilation efficiency and peak VO2 in patients with CHF not taking ACE inhibitors, but it worsens the pulmonary diffusion for carbon monoxide, VO2, and the ventilatory response to exercise in the presence of ACE inhibition. This may be relevant in patients with CHF from ischemic heart disease. Whether the same may be true of smaller aspirin doses was not investigated in this study. (Am Heart J 1999;138:254-60.)
See related Editorial on page 193. The effects of prostaglandins include preservation of endothelial integrity, capillary tone, and permeability.1 Because bradykinin-mediated prostaglandin synthesis is quite susceptible to cyclooxygenase blockers such as From the Istituto di Cardiologia dell’Università degli Studi, Centro di Studio per le Ricerche Cardiovascolari del Consiglio Nazionale delle Ricerche, Fondazione “Monzino”, IRCCS. Supported in part by a grant from the National Research Council, Rome, and the Monzino Foundation, Milan. Presented in part at the 70th American Heart Association Scientific Sessions, Orlando, Fla, November 9-13, 1997. Submitted February 23, 1998; accepted June 17, 1998. Reprint requests: Marco Guazzi, MD, Istituto di Cardiologia, Via C. Parea, 4, 20138 Milan, Italy. E-mail: [email protected] Copyright © 1999 by Mosby, Inc. 0002-8703/99/$8.00 + 0 4/1/96660
aspirin, these agents are used for exploring the pathophysiologic importance of prostaglandins in various clinical settings.2 Congestive heart failure (CHF) is an example of prostaglandin synthesis activation,3 and some of the benefits of angiotensin-converting enzyme (ACE) inhibitors in patients with CHF may be interfered with by cyclooxygenase blockers.4-6 Thus the question has emerged of whether in the case of potential clinical indication, aspirin is safe when the heart is failing and ACE inhibitors are included in the therapy.7 There seems to be the premise for an exposure of the lungs to the counteractive activity of aspirin because the luminal surface of the lung vessels is an important site of prostaglandin production, release, and metabolism.8 An example may be the improvement produced by enalapril of pulmonary diffusion for carbon monoxide in CHF and its disappearance with the administration of aspirin.9 Because abnormal ventilation is a major cause of exercise disability in CHF,10 it seems reasonable to wonder
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Table I. Drug treatments and hemodynamic and respiratory data at rest in groups 1 and 2 in the run-in period and after aspirin combination
Run-in No. of patients Enalapril (mg/d) Furosemide (mg/d) Digoxin (mg/d) LV ejection fraction (%) Right ventricular systolic pressure (mm Hg) FEV1 (L) % predicted VC (L) % predicted DLCO (mL/min/mm Hg) % predicted Aspirin Aspirin (mg/d) Enalapril (mg/d) Furosemide (mg/d) Digoxin (mg/d) LV ejection fraction (%) Right ventricular systolic pressure (mm Hg) FEV1 (L) % predicted VC (liters) % predicted DLCO (mL/min/mm Hg) % predicted
Group 1
Group 2
18 20 75 ± 50 0.20 ± 0.7 35 ± 6 28 ± 2
8 — 60 ± 45 0.17 ± 0.7 27 ± 8 31 ± 3
2.6 ± 0.5 85.5 ± 17 3.1 ± 0.6 76 ± 14 22 ± 6 80 ± 16
2.6 ± 0.5 85.5 ± 12 3.2 ± 0.6 78 ± 10 20 ± 4 72 ± 15
325 20 75 ± 50 0.20 ± 0.7 33 ± 7 30 ± 3
325 — 60 ± 45 0.17 ± 0.7 28 ± 6 32 ± 4
2.6 ± 0.5 85.5 ± 15 3 ± 0.6 75 ± 14 19 ± 6* 72 ± 14*
2.6 ± 0.4 82.5 ± 15 3.2 ± 0.6 78.5 ± 11 20 ± 5 72 ± 15
Values are mean ± SD. *P < .05 vs the run-in period.
whether aspirin may disturb pulmonary function and exercise capacity in CHF, at least in subjects who are receiving ACE inhibitors. This study was aimed at probing this possibility by simply giving aspirin to patients with CHF whose current therapeutic regimen did or did not include an ACE inhibitor.
Methods Patients We investigated consecutive patients referred to the Institute of Cardiology, University of Milan, for evaluation of chronic heart failure. They were included in the study if they did not have a history (>10 years) of smoking; had not received aspirin or other cyclooxygenase inhibitors in the previous 3 months; did not have joint disease or peripheral vascular disease that limited exercise; or had forced expiratory volume in 1 sec of >70% of predicted normal value. We assessed 20 patients with stable CHF in New York Heart Association (NYHA) class II to III attributable to idiopathic cardiomyopathy whose current therapeutic regimen included an ACE inhibitor (group 1, mean age 61 ± 7 years) and 8 similar patients (group 2, mean age 60 ± 4 years) who had not received ACE inhibitors in the previous 3 months. Two patients in each group were women. Patients in group 1 had
Figure 1
Study design.
been taking ACE inhibitors from at least 2 years before the study. Informed consent was obtained from each patient and the study design was approved by the Ethics Committee of the Institute of Cardiology, University of Milan.
Pulmonary function tests Measurements of forced expiratory volume in 1 second (FEV1), vital capacity (VC), maximal voluntary ventilation (MVV), and diffusing lung capacity for carbon monoxide (DLCO) were made with the Sensor Medics 2200 Pulmonary Function Test System. Measured diffusing capacity was corrected for anemia by the equation of Cotes et al.11 DLCO was measured in triplicate, with washout intervals of at least 4 minutes (the average was taken as the final result), in a sitting position with a standard single-breath technique with 0.28% carbon monoxide as a test gas. These data are expressed in absolute values and as a percentage of predicted normal values on the basis of standard nomograms incorporating age, sex, height, and weight.
Exercise testing with expiratory gases Patients exercised while sitting on an isokinetic bicycle ergometer with contemporary measurements of respiratory gases; an individualized ramp test was utilized with the ramp rate set to elicit a test duration of approximately 10 minutes. Individual maximal oxygen uptake was considered during a baseline test for determining the ramp rate. Exercise was discontinued when the patient was unable to maintain the imposed workload because of dyspnea or fatigue (symptomlimited exercise). Anaerobic threshold was defined by V-slope analysis. Expired carbon dioxide, oxygen, and volume were measured at rest and throughout exercise with a single-breath analysis with model 2900 from Sensor Medics. Ventilation was assessed by correlating minute ventilation with minute carbon dioxide production (VE/VCO2). Oxygen consumption at peak exercise (peak VO2) and VO2 at the anaerobic threshold are expressed as the oxygen consumption during the 30 seconds in which the examined event occurred. The ratio of the rate of aerobic respiration increase (δVO2 to the rate of watt of
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256 Guazzi, Pontone, and Agostoni
Figure 2
Peak VO2 and tidal volume (VTp) at peak exercise, exercise tolerance time (TT), and ratio of ventilation to carbon dioxide production (VE/VCO2) at 1 L in group 1 at the end of run-in period (Pre) and after (Post) 8 weeks of administration of aspirin. Triangles, NYHA class II; circles, NYHA class III; *P < .01 vs before aspirin; #P = .02 vs before aspirin.
work (δWR) increase during exercise was taken as an index of the aerobically regenerated adenosine triphosphate.10
Hemodynamic evaluation A phased-array echocardiographic Doppler system (Model Sonos 2000 Hewlett Packard), equipped with 25- or 35-MHz transducers for M-mode and 2-dimensional recording and 2.0or 2.5-MHz transducers for Doppler echocardiography, was used for assessing right ventricular systolic pressure and left ventricular ejection fraction according to Simpson’s rule.
maximal exercise test were repeated. After completion of this part of the study, enalapril (10 mg twice daily) was added to furosemide and digoxin in group 2 as a routine antifailure therapy. These patients regularly attended our outpatient heart failure clinic; they repeated pulmonary and exercise testing after an interval of 3 to 5 months, during which treatment was kept constant. Then aspirin (325 mg daily) was combined again and a reevaluation was carried out within 4 weeks. Investigators performing the tests were blinded to the drug administration and results of the previous tests.
Statistical analysis Study design Fifty percent of patients in groups 1 and 2 were in NYHA class II; the remaining patients in both groups were in class III (Figure 1). Two patients in group 1 did not complete the study for personal reasons, and their data were not included in the results. In the 2 week run-in period, each patient was twice subjected to pulmonary function evaluation and maximal exercise test: once at the beginning (for familiarization with the procedure) and once at the end of run-in (control measurements). Optimal doses of furosemide and digoxin were continued in both groups and the ACE inhibitor used in group 1 was enalapril (10 mg twice daily). After run-in, aspirin (325 mg daily) was given for 8 weeks; at the end of this period pulmonary function evaluation and a
Data are expressed as mean ± 1 SD. The effects of aspirin on variables at rest and variables recorded during exercise were analyzed by 2-way analysis of variance for repeated measures. Significant differences were further analyzed with the paired and unpaired t test and, as appropriate, with Bonferroni’s correction. Statistical significance was defined as P < .05. Linear regression analysis was used to examine the correlation between aspirin-induced changes in peak VO2 and the relation of minute ventilation with minute carbon dioxide production.
Results Table I reports NYHA functional class, therapeutic, hemodynamic, and spirometric data in patients in groups
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Figure 3
Peak VO2 and tidal volume (VT p) at peak exercise, exercise tolerance time (TT), and ratio of ventilation to carbon dioxide production (VE/VCO2) at 1 L in group 2 at the end of run-in period (Pre) and after (Post) 8 weeks of administration of aspirin. Triangles, NYHA class II; circles, NYHA class III.
1 and 2 at the end of run-in and in the next 8 weeks, during which aspirin was given according to the study design depicted in Figure 1. There were no group differences in the baseline, and DLCO level in group 1 was the only variable that worsened during this interval with the addition of aspirin. Figures 2 and 3 show that aspirin was deleterious when added in the presence (group 1, Figure 2) and not in the absence (group 2, Figure 3) of the ACE inhibitor enalapril. The effects of aspirin in group 1 consisted of a decrease in exercise tolerance time, peak exercise oxygen uptake and tidal volume, and of an increase in the relation of minute ventilation to carbon dioxide production. The response to aspirin was similar in patients in NYHA class II and III. The variations were not associated with changes in peak exercise heart rate, blood pressure, oxygen uptake per cardiac beat (oxygen pulse, a parameter reliably reflecting variations in stroke volume during exercise), ratio of δVO2 to δWR, and in the oxygen consumption at the anaerobic threshold (Table II). Figure 4 shows that in patients receiving enalapril there was an inverse correlation between the variations with aspirin in peak VO2 and those in the ratio of minute ventilation to minute carbon dioxide production at peak exercise. Table III reports the means of DLCO, peak VO2, peak VT, and VE/VCO2 at 1 L
in group 2 at the end of run-in, after aspirin alone, after enalapril alone, and in combination with aspirin. It is shown that when patients were taking ACE inhibitors, aspirin exerted a negative influence on these variables.
Discussion This study demonstrates that aspirin worsens the ventilatory gas exchange and exercise capacity in patients with CHF taking ACE inhibitors. Exercise is probably the most powerful physiologic stimulus capable of increasing the vascular prostacyclin production rate through an endothelial shear stress mechanism.12 Prostaglandins have been recognized to be involved in determining the physical performance of normal subjects.13
Previous studies In chronic heart failure the augmented production of vasodilating prostaglandins mediates a regional and systemic vasodilating activity, attenuates neurohumoral activation, and counteracts vasoconstriction induced by angiotensin II,14 norepinephrine,15 and endothelins.15 Cyclooxygenase inhibition causes a loss of these counterregulatory mechanisms and may favor a progressive deterioration of patients with advanced heart failure.3
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258 Guazzi, Pontone, and Agostoni
Table II. Heart rate, blood pressure, and oxygen uptake during exercise in groups 1 and 2 at the end of the run-in period and after aspirin combination
Run-in Heart rate peak (beats/min) Blood pressure peak (mm Hg) Systolic Diastolic Oxygen pulse peak (mL/beat) VO2 at anaerobic threshold (mL/min/kg) δVO2/δWR peak (mL/min/w) Aspirin Heart rate peak (beats/min) Blood pressure peak (mm Hg) Systolic Diastolic Oxygen pulse peak (mL/beat) VO2 at anaerobic threshold (mL/min/kg) δVO2/δWR peak (mL/min/w)
Group 1
Group 2
142 ± 9
143 ± 12
172 ± 17 115 ± 15 9.5 ± 3 11 ± 2
175 ± 22 120 ± 15 9±4 11 ± 3
7.5 ± 1.0
7.5 ± 1.2
139 ± 11
141 ± 10
176 ± 17 116 ± 14 10.2 ± 3 12.2 ± 2
180 ± 20 120 ± 14 9.7 ± 3 11.5 ± 3
7.3 ± 1.2
7.4 ± 1.2
Figure 4
Relation between changes (δ) from run-in with aspirin in peak VO2 and changes in VE/VCO2 in group 1.
Values are mean ± SD.
Table III. Pulmonary diffusion, exercise oxygen uptake, tidal volume and ventilation in group 2 in the run-in period and after administration of aspirin, enalapril, and the combination
DLCO (mL/min/mm Hg) Peak VO2 (mL/min/kg) Peak tidal volume (mL/min) VE/VCO2 1 L
Run-in
Aspirin
Enalapril
20 ± 4 17.3 ± 4 1.70 ± 0.3 39 ± 8.2
20 ± 5 17.1 ± 3.8 1.64 ± 0.3 38.1 ± 8.1
23 ± 3* 20 ± 3* 1.80 ± 0.4* 32 ± 8*
Enalapril + Aspirin 20.4 ± 4† 17.5 ± 3† 1.68 ± 0.4† 39.3 ± 8†
Values are mean ± SD. *P < .01 vs run-in period. †P < .05 vs enalapril.
Although a prostaglandin-mediated activity seems to be a common final mechanism of action of several cardiovascular drugs, including diuretics, nitrates, and nitroprusside, ACE inhibitors peculiarly potentiate the cascade of this system. This study addresses the clinical relevance of a potentiation of these mediators through ACE inhibition and of a counteraction, as occurring with the combination of aspirin, in the presence of left ventricular dysfunction and exercise intolerance.
This study Several considerations support the interpretation that a link exists between the beneficial action of enalapril on respiratory function and exercise performance and counteraction of aspirin, and that prostaglandins are the mediators of this link. The 2 groups of patients had similar clinical characteristics, ejection fraction, pulmonary function, and right ventricular systolic pressure.16 That inability to show an effect of aspirin in patients not taking ACE inhibitors (group 2) may have been caused by the small
number of subjects studied is convincingly disproved by the occurrence of an inhibitory activity when aspirin was reintroduced after the combination of enalapril. According to the inclusion of the ACE inhibitor in the therapy, a decline in pulmonary diffusion was noted with aspirin. This could have been caused by removal of an action on alveolar-capillary membrane facilitating conductance or to a decrease in pulmonary capillary blood volume from the known vasodilating properties of prostaglandins. These changes were associated with a decline in peak exercise oxygen uptake, in agreement with the concept that pulmonary diffusion limitation may be a mediator of the exercise oxygen uptake.9,17 When patients were receiving ACE inhibitors, pulmonary gas exchange efficiency was also depressed by aspirin. In fact, tidal volume during exercise was reduced and the ventilatory requirement for given carbon dioxide production was increased. That the lungs are sensitive to prostaglandins and exercise unmasks their involvement is supported by experimental obser-
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vations showing that increase in blood flow velocity (causing an increase in shear stress) contributes to prostaglandin production in the pulmonary circulation and that a preliminary infusion of indomethacin counteracts this effect.18 It seems, therefore, that in patients with heart failure receiving ACE inhibitors lung prostaglandin production is enhanced and its inhibition with aspirin is deleterious. An important participation of changes in the systemic hemodynamics during exercise as a cause of exercise intolerance seems unlikely because of the absence of significant variations in blood pressure, heart rate, and oxygen pulse at peak exercise. Metabolic reasons were also seemingly excludable because oxygen consumption at the anaerobic threshold and the ratio of peak δVO2 to peak δWR did not vary with aspirin. Although it has been shown that aspirin may reduce blood flow to working muscles,19 the possibility that a reduced efficiency in gas exchange performance may be a substrate for the reduced exercise capacity is supported by the close inverse correlation that was found between variations in peak VO2 and changes in the ratio of minute ventilation to carbon dioxide production.
Clinical implications Thus this study expands the observations made in a previous report from our group.9 It shows that (1) an interference with the enhanced prostaglandin release has well-defined clinical correlates that are similar in NYHA functional class II and III; (2) the prostaglandin stimulating activity of ACE inhibitors is sustained (they, in fact, had been part of the therapeutic management for at least 2 years in group 1); and (3) aspirin counteraction is unrelated to the duration of the ACE inhibitor therapy. The evaluation of the prognostic significance of the counterregulatory effect of aspirin versus ACE inhibition is not an easy item. Aspirin improves the outcome in the acute phase of unstable angina or myocardial infarction20 and is a cornerstone in the primary and secondary prevention of ischemic events.21 ACE inhibitors, on the other hand, improve survival rate,22 quality of life, and exercise performance23 in patients with left ventricular dysfunction. Because ischemic heart disease is a predominant cause of heart failure, it is expected that this drug combination exerts additive beneficial effects. However, a retrospective analysis of the CONSENSUS II trial4 has given support to the finding previously emerged in the SOLVD trial,3,24 that the survival rate curve was different when analysis was performed according to aspirin use or nonuse in patients taking ACE inhibitors. Hall et al5 demonstrated an attenuating action of aspirin on the acute hemodynamic changes with enalapril. Other studies,25 on the contrary, have pointed out that the vasodilating effects of ACE inhibitors are mainly related to blockade of the angiotensin system and that a contrasting effect on vas-
Guazzi, Pontone, and Agostoni 259
cular resistance remains controversial. According to findings in this mid-term exercise study, aspirin subtracts the beneficial action of ACE inhibitors on peak VO2, an independent prognostic predictor in patients with heart failure.26
Limitations Interpretation of findings in this study is potentially weakened by the lack of measurements of plasma prostaglandins. These compounds have a very short half-life (less than 3 minutes) and are not reliably measurable. In addition, their production rate is tissue dependent, and monitoring changes in the pulmonary microvessels during exercise is a difficult task. Investigations in human beings and animals are mainly restricted to an analysis of variations deriving from prostaglandin blockade with cyclooxygenase inhibitors. Whether a lower dose of aspirin would equally show an antagonism remains to be defined.
Conclusions This study indicates that cyclooxygenase prostaglandin blockade with aspirin does not affect ventilation and oxygen consumption during exercise in patients with CHF not taking ACE inhibitors but worsens the pulmonary diffusion capacity and makes the ventilatory response to exercise (tidal volume, ventilation to carbon dioxide production) less effective in those who do, regardless of the duration of ACE inhibition.
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